The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial

Abstract

Background:Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity.Methods:We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0–1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1–14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m−2) was administered on day 1 starting with cycle 2. 3′-Deoxy-3′-18F-fluorothymidine (18F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma.Results:The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing 18F-FLT-PET scans showed increases (23–92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAFV600E/K patients had significantly worse PFS than patients without these mutations.Conclusions:Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3′-Deoxy-3′-18F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

BRAF mutational status as a prognostic marker for survival in malignant melanoma: a systematic review and meta-analysis

“…As this meta-analysis excluded studies with patients treated with a BRAF and MEK inhibitor or a checkpoint inhibitor, only eight studies, with patients treated with chemotherapy, immunotherapy or surgery were pooled. Except for one small study [35] with 38 patients that showed significantly poorer PFS (HR: 5.5) in BRAF mutated versus WT patients, no prognostic impact on PFS was reported. The pooled effect showed that BRAF mutational status had a neutral role on PFS.…”

Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8+ effector T cell responses

“…In this regard, drugs targeting vascular endothelial growth factor (VEGF) or its receptor have shown encouraging clinical outcomes in early-phase studies when combined with chemotherapy, 49 demonstrating survival extension in patients with metastatic melanoma. 50 Immune targeting of the NOTCH antagonist delta-like 1 homolog (DLK1) has also shown promising results in normalizing the vasculature in the TME of renal cell carcinoma mice models. 51 Furthermore, while in the present study Rictor ¡/¡ DC promoted the loss of MDSC in the TME, the negative impact of Treg on type-1 CD8…”

Developments in targeted therapy in melanoma

“…52 However, these result warrants further testing in randomized phase III trials. On the other hand, the multi-kinase inhibitor Lenvatinib (E7080) achieved limited responses both in monotherapy and in combination with TMZ in the phase I setting.…”